Cancer is caused by uncontrolled abnormal cell growth, and cancer cells infiltrate into normal tissues or organs around to destroy them and take over the places for its proliferation, even resulting in taking the life of an individual.
Although a remarkable progress has been made in studies of an oncogene and a tumor suppressor gene as well as regulations of cell cycle or apoptosis, cancer development is still on the increase as civilization advances. The treatment of cancer, for now, depends on surgical operation, radiotherapy and chemotherapy including administration of over 40 kinds of anticancer agents having strong cytotoxicity. However, those treatment methods are limited in use, meaning they are applicable to only cancer patients in early stage or with some specific cancers. So, cancer induced death is also on the increase.
The biggest threat of cancer to a life is metastasis, leading an individual to death. Surgical operation has been widely performed to treat cancer but it is not much help to treat transferred cancer cells, even after primary cancer has been removed. Therefore, conquering a cancer means a fight with metastasis.
Cell migration is involved in many stages of metastasis complicatedly; first, it is involved in early stage when cancer cells are transferred from the birth place into a blood vessel by way of extracellular matrix (ECM), second, it plays a role in transfer of cancer cells from the second metastatic tissues to outside blood vessels, and next, it is involved in the movement of vascular endothelial cells in neo-vasculatures.
The polarity of a transferring cell is induced by a signal receptor activated by a cell migrating inducer. The front end of a cell is attached to extracellular matrix by integrin with extension of cell membrane by polymerization of actin. At this time, strong contraction is caused between actin polymers by the bond of myosin with an actin polymer, giving a cell strong contraction. The direction of cell migration is determined by the difference between front end and back end of a cell in adhesive power. When adhesion of front is bigger than that of rear, the rear part of a cell is apart from extracellular matrix, making the cell move forward. On the contrary, when adhesion of front is weaker than that of rear, a cell stays at the place. Protrusions (Lamellipoda, Filapoda) having different structural morphology were formed by a signal transmission molecule activated by cell migrating signal receptor. Such different protrusions include actin in the form of a string and a set of protein having different structures and signals, and further lead reciprocal relation with ECM [Peter Friedl, et al., Nature Cancer Review, 2003, 3: 362].
The goal of an anticancer agent tracing the movement of cancer cell is also inhibiting metastasis. Inhibition of cell migration is not the final goal, but must be a realistic approach to extend life of a cancer patient. A tumor in primary stage can be simply and completely removed by surgical operation, regardless of the region, but once it transfers into other regions, surgical operation is not much help. If diagnosis is made after primary stage, cancer cells will be spread through blood vessels already and further more, a tiny colony might be generated at the second or at the third region. In that case, successful treatment of cancer cannot be expected by surgical operation only. Actually, there are lots of cases giving up surgical treatment because of metastasis. In those cases, an anticancer agent is administered, under the condition of inhibiting the movement of cancer cells, to induce apoptosis of cancer cells to extend life span of a patient. Thus, the development of a cancer cell movement inhibitor leads to the development of a novel anticancer agent and can be important assets for the study of cell movement.
Angiogenesis means whole process forming a new blood vessel from an existing blood vessel, and is accompanied indispensably by metastasis to a malignant tumor [Jack L. Arbiser, et al., Proc. Natl. Aced. Sci. USA, 1997, 94: 861]. Angiogenesis inhibitor has drawn our attention as one of attractive approaches to develop a novel anticancer agent. And the reasons of the importance or the attraction of angiogenesis inhibitor are as follows; first, angiogenesis is indispensable for primary tumor or metastatic tumor which means cancer cells are supplied with nutrition and oxygen through newly formed blood vessels and not growing larger than 1˜2 mm3 without the supply. During angiogenesis, primary tumor cells infiltrate into blood vessels and move to other regions, resulting in metastatic tumor. So, an angiogenesis inhibitor can be applied to any solid tumor. Second, the conventional chemotherapy is a way to treat cancer by taking advantage of fast growing speed of cancer cells, so that it shows cytotoxicity not only to cancer cells but also to bone marrow cells or gastrointestinal cells having comparatively fast turn over. But, an angiogenesis inhibitor carries less side effects even after long-term administration. In addition, another problem of the conventional chemotherapy is resistance since it is targeting transformed cancer cells. But, an angiogenesis inhibitor aims at treating a normal blood vessel, creating less chance of resistance. Third, one blood vessel is able to deliver nutrition and oxygen to hundreds of cancer cells, so even one-time inhibition of angiogenesis affects a great number of cancer cells. The advantage of drug delivery is the last reason. Precisely, under the conventional chemotherapy, an anticancer agent is to flow out of a blood vessel to kill cancer cells. On the contrary, an angiogenesis inhibitor can directly contact vascular endotherial cells, making drug delivery easy.
Dr. Folkman at Harvard Medical School hypothesized in early 1970s that a cancer cell secrets a specific factor to induce angiogenesis. After that, it was proved by many research groups including Dr. Folkman's team that angiogenesis plays an important role in metastasis, and further an angiogenesis-inhibiting factor was identified [J. Folkman, et al., Science, 1987, 235: 442]. In 1985, angiogenin, an angiogenesis inducer, was first found in secreting fluid of human adenocarcmoma cells by Dr. Vallee, et al., at Harvard medical school. A solid tumor is supplied with nutrition and excretes wastes through newly formed blood vessels around to be growing and cancer cells transfer to other regions such as lung, liver, etc., through circulatory system [L. A. Liotta, et al., Cell, 1991, 64: 327]. It was also reported that angiostatin, an angiogenesis inhibitor, suppresses growth and transfer of lung cancer cells [M. S. O'Relly, et al., Cell, 1994, 79: 315]. In early years of cancer study, it had been believed that cancer cells were anaerobic tissues. But, it is now believed by the above reports that nutrition and oxygen supply is essential for the growth of a tumor.
German research scientists reported in 1993 that they separated a chemical compound inhibiting angiogenesis from a bean [T. Fotsis, et al., Proc. Natl. Acad. Sci. USA, 1993, 90: 2690]. The compound was named ‘genistein’, which has been expected to suppress the growth of a small malignant tumor. The number of prostatic cancer patients among Japanese taking beans a lot is less than that of Westerners. But, the number of prostatic cancer patients among Japanese immigrants in western countries increased fast since they no more took beans frequently [F. M. Uckun, et al., Science, 1995, 267: 886]. Another study group lead by Dr. Fatih M. Uckun at University of Minnesota reported in 1995 that they prepared a medicine by combining a monoclonal antibody with genistein and administered the medicine to a mouse transplanted with human BCP leukemia cells, resulting in 99.999% destruction of human BCP leukemia cells [F. M. Uckun, et al., Science, 1995, 267: 886].
Thus, an angiogenesis inhibitor is not only a relevant factor to explain the mechanism of cancer cell growth but also used effectively for the prevention and the treatment of cancers and further for the treatment of angiogenesis related diseases such as diabetic retinopathy, rheumatoid arthritis, chronic inflammation, hemangioma, etc. For that reason, an angiogenesis inhibitor has been a major target of study in the field of biological science as well as in the field of industry.